We propose to design, build, and evaluate the Scanner Approaching in Vivo Autoradiographic Neuro Tomography (SAVANT), a next generation PET scanner for ultra-high resolution imaging of the human brain using hardware advances developed by members of our collaborative team to achieve unprecedented spatial resolution and count rate capabilities. The system will have a volumetric resolution close to 1 mm3 (isotropic spatial resolution close to 1 mm), which is approximately 27 fold better than the best dedicated brain PET scanners and 125 fold better than general purpose PET scanners. Such an improvement will allow visualization and quantification of in vivo physiological events as never before possible, such as deposition of tau neurofibrillary tangles in the entorhinal cortex in the prodromal stages of Alzheimer's disease and dopamine transporter concentration in the substantia nigra and ventral tegmental area. This will allow the detection and quantitation of brain disease at a much earlier stage, decades before onset of clinical symptoms, and permit the study of key structures in neurotransmitter systems that currently cannot be imaged accurately with PET. The proposed high resolution PET scanner will be validated in phantom studies and performance evaluated in healthy volunteers.